MATERNAL PKU AND OTHER METABOLIC DISORDERS

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MATERNAL PKU LONGER TERM OFFSPRING OUTCOME
RELATED TO PRENATAL AND POSTNATAL FACTORS

• Harvey L. Levy, MD, Susan E. Waisbren, PhD,
• Fran Rohr, MS, RD, Vera Anastasoaie, Stephanie
  Petrides
• Boston Childrens Hospital
• Harvard Medical School

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Dr. Levy has the following disclosures

• Maternal PKU Study, NPKUA
• Maternal PKU Study, Milton Fund
• Enzyme Therapy for PKU, BioMarin
• 
  Pharmaceuticals
• GMP therapy for PKU, FDA
• Urea Cycle Disorders, NIH

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• Dr. Charles E. Dent Richards made a chance
  observation from a phenylketonuric mother at the
  mental defective colony in Caterham, near London.
  She had three children .. All three
  children were mentally retarded from birth but
  had no abnormal amino acids in their urine. We
  felt that it might well have been the toxicity of
  the mothers high blood phenylalanine level that
  damaged their brains in utero.
• From Discussion at the 23rd Ross Pediatric
  Research Conference 1957

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• PAH
• Phenylalanine Tyrosine
• BH4
• Phenylpyruvic Acid
• Phenyllactic Acid Phenylacetic Acid

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MATERNAL PKU A PROBLEM BORN OF SUCCESS
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Aims of the Study

1. Longer term medical and intellectual outcome of
   the offspring
2. Psychological-emotional-social functioning of the
   offspring
3. Medical-nutritional-emotional status of the
   mothers
4. Relative roles of metabolic control in pregnancy
   and postnatal maternal stimulation in offspring
   outcome

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The Sample

• 27 mothers ranging from 23-48 (average age is 40)
• 48 offspring ranging from 2 months-26 years
  (average age is 9 years)
• 0-2 10 subjects
• 3-6 15 subjects
• 7-11 8 subjects
• 12-18 12 subjects
• gt18 3 subjects

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Measures Used In Study

• IQ (mothers and offspring)
• Executive functioning (mothers and offspring)
• Prevalence of Anxiety/Depression/ADHD (mothers
  and offspring)
• Physical exam (mothers and offspring)
• Home Scale--measure of home environment
  (offspring)
• Nutrition assessment (mothers)
• Labsincluding blood Phe (mothers)
• Photos to look at dysmorphology (mothers,
  offspring, and fathers if possible)

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Offspring outcome was determined by ABAS

• ABAS- Adaptive Behavior Assessment System
• (questionnaire completed by mother that includes
  10 skills areas of offspring)
• ABAS correlates with offspring IQ
• n27, r0.73, plt0.0001
• ABAS correlates with offspring DQ
• n11, r0.77, p0.005

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Prenatal Metabolic Control

• Started diet prior to pregnancy 76
• In metabolic control prior to pregnancy 41
• Control during pregnancy
• Excellent 41 (11)
• On diet prior, blood phe lt 6 mg/dL throughout
• Good 35 (9)
• On diet prior, blood phe lt6 mg/dL by 10 weeks
• Fair 14 (4)
• Blood phe lt 10 mg/dL by second trimester
• Poor 10 (3)
• Blood phe in control in third trimester or never

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Maternal Postnatal Diet

• Mothers currently on diet 52 (14/27)
• On diet taking medical food and restricting phe
  
• Maternal Blood Phe
• Average 1176 umol/L (19 mg/dL)
• Range (386-1934) (6-32)

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Prenatal Treatment vs. Offspring Outcome

• Maternal Offspring ABAS
• Pre-conception 9816
• Post-conception 9222

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Current Maternal Dietary Status vs. Offspring
Outcome

• Dietary Status Offspring ABAS
• On diet 10316
• Off diet 9712

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Mothers Prenatal and Postnatal Diet vs.
Offspring ABAS
Excellent Control Not Excellent Control
On Diet n10 11218 lt850 n14 9715 lt853
Off Diet n8 1027 lt850 n13 8920 lt854
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Conclusions

• Longer term follow-up of offspring from treated
  maternal PKU pregnancies confirms that outcome is
  usually within normal limits
• Offspring outcome is not only IQ but also
  function (social, behavioral) as measured by
  ABAS
• Optimal offspring outcome requires not only
  prenatal metabolic control but also postnatal
  stimulation
• Good postnatal stimulation requires maternal
  continuation of diet

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Effects of Glycomacropeptide, Amino Acid
Casein Diets on Osteopenia in PKU Mice

• Denise M. Ney, PhD, RD
• Professor of Nutritional Sciences
• Waisman Center
• University of Wisconsin-Madison

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Disclosure

• D Ney is a co-inventor on US Patent Application
  US-2010-0317597, GMP Medical Foods for
  Nutritional Management of PKU, which is held by
  the Wisconsin Alumni Research Foundation and
  licensed to Cambrooke Foods, LLC. A percentage
  of all royalty payments is awarded to the
  inventors.
• D Ney has received consulting income from
  Cambrooke Foods and BioMarin.

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UW-Madison PKU Bone Research Team
Denise Ney Robert Blank Sangita
Murali Patrick Solverson

• Funding National PKU Alliance USDA Hatch
  Grant

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Background

• PKU is associated with low bone mass, or
  osteopenia, and fractures in early adulthood.
• 57 of 28 patients had osteopenia/osteoporosis
• Perez-Dueñas et al. Acta Paediatr 91800, 2002
• Reduced bone mineral density (BMD) in PKU is
  present from an early age onward and it cannot be
  predicted by plasma phe levels.
• 20 of 53 patients studied had osteoporosis
• de Groot et al. Mol Genet Metab 101566, 2012

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What causes skeletal fragility in PKU?

• The fundamental question is whether reduced BMD
  is inherent to PKU or secondary to its dietary
  management.
• In order to isolate the contributions of the PKU
  genotype itself and dietary treatment of PKU we
  have conducted a factorial experiment in PKU
  mice.

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Objective Design

• To determine how the PKU genotype and the source
  of dietary protein affect growth, body
  composition and bone development.

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PKU WT Mice Housed With Same Sex Littermates
?phe GMP ?phe AA ?phe Casein
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GMP is a natural whey protein produced when
making cheese. Pure GMP contains no phe.
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Growth
Solverson, P et al Am J Physiol Endocrinol Metab
302E885-95, 2012
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Metabolic Phenotyping Platform
?Food water intake ?O2 consumption
CO2 production
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PKU mice show increased energy expenditure with
casein diet
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GMP Diet Normalizes Food Intake in PKU Mice
Values with different letter superscripts are
significantly different, plt0.05
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AA Diet Increases Kidney Workload in both WT and
PKU Mice
Values with different letter superscripts are
significantly different, plt0.05
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Does PKU increase energy needs?

• Resting energy expenditure is 5-10 higher in
  adolescent females with PKU than that predicted
  by standard equations.
• J Am Diet Assoc 110922-25, 20101
• Am J Clin Nutr 62797-804, 1995
• Reduced growth occurs in children with PKU
• Mol Genet Metab 10199-109, 2010
• J Pediatr 261-11, 2002

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Dual Energy X-Ray Absorptiometry (DXA)
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PKU mice show reduced whole-body bone
mineralization compared to WT mice
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Femur Strength 3 Point Loading Test
Loading force being applied to a mouse femur
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Load-Displacement Curve
Displacement, mm
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PKU mice show bones that are brittle and break
easily
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PKU mice show reduced femoral bone mineralization
compared to WT mice
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How the casein, AA and GMP diets affect bone size
and strength?
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GMP Increases Bone Size in PKU WT Mice
Casein
AA
GMP
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GMP Improves Bone Strength in PKU and WT Mice
Compared with AA Diet
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Summary

• PKU mice have femora that are
• brittle and weak. This suggests
• defects in both collagen synthesis
• and mineralization.
• GMP increases bone size and strength femora
  tolerate a higher max load before fracture
  compared with the AA diet.
• How does GMP work to improve bone strength in
  mice?

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What causes skeletal fragility in PKU?

• Inherent to PKU genotype and/or
• Secondary to management with an AA diet.
• Answer both genotype and diet

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Conclusion

• Skeletal fragility is inherent to the PKU
  genotype and is attenuated by a GMP compared with
  an AA diet in mice.
• Future research is needed to determine if
  improved low-phe diets containing GMP reduce
  skeletal fragility in human PKU.

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Take Home Message How can bone health be
improved in PKU?

• Follow a low-phe diet to improve growth and bone
  development
• Include weight bearing exercise each day

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